Radiation-induced lung injury

RILI is a dose-limiting toxicity encompassing a spectrum of pulmonary complications following thoracic radiotherapy that can affect patients treated for lung, breast, esophageal, or mediastinal malignancies, as well as those receiving total body irradiation. It includes acute radiation pneumonitis, typically occurring within 6 months of treatment, and chronic radiation fibrosis, which develops months to years later. A third variant, radiation recall pneumonitis, is characterized by acute inflammation in previously irradiated lung tissue following exposure to certain systemic agents, such as chemotherapy or immune checkpoint inhibitors.

RILI is triggered by damage to the alveolar-capillary barrier following ionizing radiation. The injury involves direct DNA damage and the generation of reactive oxygen and nitrogen species, which account for most of the tissue damage. Type I pneumocytes and vascular endothelial cells are especially vulnerable. Mitochondrial DNA damage plays a key role in activating inflammatory cascades. Within hours to days, vascular congestion, leukocyte infiltration, and pneumocyte apoptosis cause increased permeability and edema. Early cytokines include TNF-α, IL-1, IL-6, PDGF-β, and bFGF. A second wave at 6-8 weeks involves oxidative stress, hypoxia, and TGF-β1 expression. The latent phase features goblet cell hyperplasia and epithelial dysfunction. Pneumonitis typically manifests in the exudative phase (3-12 weeks), marked by alveolar collapse, hyaline membrane formation, and type II pneumocyte proliferation. Later phases involve fibroblast activation, extracellular matrix accumulation, and interstitial fibrosis driven by TGF-β1 and chronic hypoxia. Inflammatory cells such as neutrophils and macrophages contribute to sustained injury through adhesion molecules (ICAM-1, PECAM-1) and cytokine signaling. This perpetuates alveolar damage and fibrosis, leading to reduced lung compliance and gas exchange. Radiation recall pneumonitis may occur after systemic therapy, such as taxanes, anthracyclines, or immune checkpoint inhibitors, triggering inflammation in previously irradiated tissue regardless of the time since radiation.

RILI is a common dose-limiting toxicity in thoracic radiotherapy. It affects patients treated for lung cancer, breast cancer, lymphoma, and those receiving total body irradiation. The overall incidence of clinically significant RILI ranges from 5% to 58%, reflecting differences in patient populations, treatment protocols, and diagnostic criteria. Modern techniques such as SBRT and intensity-modulated radiotherapy have reduced this risk through improved dose conformity.Among patients with lung cancer, the incidence of RILI is estimated at 5-25%, with higher rates observed in those receiving concurrent chemoradiation. Incidence is lower in mediastinal lymphoma (5-10%) and breast cancer (1-5%). As more patients undergo thoracic RT for definitive, adjuvant, or palliative indications, the population at risk for RILI continues to expand.

Risk factors for RILI include patient-specific, treatment-related, and dosimetric parameters. Advanced age, female sex, pre-existing lung disease (particularly interstitial lung abnormalities and COPD), poor baseline pulmonary function, and hypoalbuminemia increase susceptibility. Smoking history has shown a paradoxical association, with some studies reporting lower RILI rates in current smokers. Dosimetric factors such as mean lung dose, lung volumes receiving ≥ 20 Gy (V20), and heart irradiation are strongly associated with risk. Tumors located in the lower lung regions and larger planning target volumes further elevate risk. Concurrent or sequential systemic therapies, including chemotherapy (such as gemcitabine, paclitaxel, mitomycin), targeted agents (such as EGFR inhibitors), and immune checkpoint inhibitors, amplify pulmonary toxicity. High-dose per fraction schedules and immunotherapy-radiotherapy combinations, particularly in stereotactic protocols, have been linked to increased pneumonitis incidence.

RILI is classically divided into an acute phase, termed radiation pneumonitis, occurring within 4-12 weeks of treatment, and a chronic phase, radiation fibrosis, manifesting beyond 6 months. Radiation pneumonitis presents with dyspnea, dry cough, low-grade fever, and fatigue in 20-40% of patients. Severe cases may involve hypoxemia and respiratory failure. Physical findings are often nonspecific but may include crackles, pleural rubs, or dullness on percussion. Radiographic abnormalities, including ground-glass opacities and consolidation within the radiation field, evolve with disease progression and can precede symptoms. CT is more sensitive than chest radiographs. Pulmonary function tests typically reveal a restrictive defect with reduced diffusing capacity. Bronchoscopy and biopsy may be necessary to exclude other etiologies such as infection or malignancy. In the chronic phase, symptoms of progressive dyspnea, reduced lung compliance, and signs of pulmonary fibrosis dominate. Severe fibrosis can lead to pulmonary hypertension and cor pulmonale. Diagnosis relies on the timing of symptoms after radiation, imaging correlation with radiation fields, and exclusion of alternative causes. High-precision techniques such as SBRT/stereotactic ablative radiotherapy are associated with lower rates of symptomatic RILI, though post-radiation scarring may mimic recurrence and requires careful interpretation.

Most cases of radiation pneumonitis are mild and self-limited, responding well to corticosteroids. However, severe cases can lead to significant morbidity, prolonged hospitalization, and, rarely, death. Chronic progression to radiation fibrosis may result in irreversible pulmonary impairment, reduced functional status, and, in extensive cases, pulmonary hypertension or cor pulmonale. Risk of long-term sequelae is higher in patients with large-volume radiation exposure, poor baseline lung function, or underlying ILD.